Production of saligenin derivatives



Patented July '21, 1953 PRODUCTION OF SALIGENIN DERIVATIVES Edgar c. Britton and James D. Head, Midland, Mich., assignors to The Dow Chemical Company; MidlamL Mich a corporation of'Delav ware V No Drawing.

This invention relates to the production of saligenin derivatives, and, more particularly, to theproduction of compounds represented by the general formula in which each of the radicals R and R is of the class consisting of hydrogenand acetyl (i. e., 3- fiuorosaligenin, 3-fluorosaligenin monoacetates and 3-fluorosaligenin diacetate) It has been known that halogens can be removed from a benzene ring by the action of hydrogen in the presence of certain catalysts. It has also been known that alcohol groups or ester groups can be reduced by theaction of hydrogen in. the presence of certain catalysts. However, so far as we are aware, it has not heretofore been known'to be possible to, remove se-' lectively only one of two difierent halogens attached to a benzene ring, 1. e., to remove a chloro radical and leave a fiuoro radical attached to the ring. Neither has it been known to be possible to effect dechlorination by the aforementioned Application December 23,1949, ,Seriali-No. 134,835

j '5 Claims, (crest- 479) ionization constant not greater than 3 10- (i. e.,

' sure is as low as about 10 pounds per square.

method without simultaneously reducing an alcohol or ester group attachedto the same benzene nucleus as the chloro group. By the present in-T vention it is possible to conducta catalytic dehalog'enation to remove the chloro group from 5- chloro-B-fluorosaligenin or from 5- chloro-3-fluorosaligenin diacetate, without removing the fluoro group, and without reducing the OH groupor an ester group.

According to-theinventiona saligenin derivae. I

tive having the general formula CHaOR in which each of the radicals R and R is of. the class consisting of hydrogen and. acetyl is de--.

' chlorinated by the action of one. mol of gaseous per square inch gauge.

a substance that forms a one normal solution having a pH higher thanabout 3.5).

The method of the invention is limited to the dechlorination of 5-chloro-3-fluorosaligenin, of

5-chloro-3 fluorosaligenin diacetate and of a 5- chloro-3-fi'uorosaligenin monoacetate; Products which result from the dechlorination are 3-fiuorosaligenin, 3-fluorosaligenin diacetate and 3- The 3 -f1uo'rosali-' genin, the 3-fiuorosaligenin diacetate and 3-fiuofluorosaligenin monoaceaates.

rosaligenin monoacetates are materials having particular utility because any of them can be used as an intermediate for the production of 3fluorosalicylaldehyde, which is a valuable compound for use in the preparation of oxygencarrying chelates (see J. Am. Chem. Soc. 68, page 2254).

The ,dechlorination is carried' out in a hydrogen atmosphere; It has been found that the dechlorination proceeds'when the hydrogen presinch gauge, but it is usually preferred that the hydrogen pressure be at least about 20 pounds It is essential that the hydrogen pressure not exceed 40 pounds per square inch gauge because undesirable side reactions proceed when a higher pressure is used. It is usually preferred that the pressure be not higher than about 30 pounds per square inch gauge. The reaction is continued until one mol of hydrogen has reacted per mol of the chlorinated saligenin derivative (e. g., until the pressure drop indicates reaction to such an extent). It is believed that palladium itself is the catalyst for the dehalogenation reaction. However;

because of the high cost of palladium it is ordinarily desired that the palladium be supplied in n n the form of a coating on some carrier. Palladir 1 4'0 hydrogen per mol of the saligeninwderivativel The dechlorination is accomplished at a .hydrogenpressure of fromoabout l0;to-.about 40, pounds perfsquare inch gauge and in the presence ofa' palladium catalyst andan acceptor forthelhye drogen ions formed by thedechlorination. Such an acceptor is a compound that reacts with the hydrogen ions to form a substance havingan um is readily available on barium sulfate, calcium carbonate or carbon, as carriers, calcium carbonate being preferred as a carrier because it tends itself to prevent undue acidity in the mixture to be'dechlorinated, carbon being preferred because such a catalyst is most easily available.

Powdered palladium itself can be used as acatalyst, but is not employed, usually; because of its high cost. The amount of catalyst that is ordi-' narily used is from about 0.1 to about 2 per cent.

(The term percent and fparts. are used herein to refer to per cent and parts by w'eighflun less otherwiseindicated.) It is usually preferred 1 to use from about 0.25 per cent to about 0.5 per' cent of the catalyst, based on the. palladium actua l present. F

The hydrogen ion acceptor that is used in the practice of the invention can be any material that reacts with hydrogen ions to form a substance having an ionization constant not greater than about 3 l0 preferably the ionization constant is not greater than about 3 3 For example, sodium acetate, which reacts with hydrogenions to form acetic acid, can be used as the hydrogen ion acceptor. Similarly, any inorganic base, or

any organic base can be us dias'the hydrogen ion.

acceptor. It is usually preferred that the acceptor be water soluble, and that a; watersolution be used. However, the reaction can he conducted in a non-aqueou organic solution that comprises a hydrogen ion acceptor. Ordinarily, the reaction is run batchwise, and it is'preferred-to-em C. and further product which precipitated v was,separated Icy-filtration and added to the original precipitate. The filtrate was then concentrated to about 700 cc. and additional l-chloro- 'alphaedimethylamino-G-fluoro-o-cresol was rec'overed'bya steam distillation. The total recovploy about one mol of the hydrogen ion acceptor per mol of the saligenin derivative; this-isthe I amount of the hydrogen ion acceptor actually required to neutralize the. hydrogen. produced. However, a substantial excess (e. g from two. to. three times the theoretical amount) may belemploycd; likewise the reaction proceeds with a deficiency, but only partial conversion ispossible.

The following examples illustrate the new process, but are notto be c'onstrued as limiting, the scope of the invention. 1

Emamplc 1' S-fluorosaligenin was produced according to the following procedure? V Aqueous sodium hydroxide (400 cc. of. lnorrnal caustic) 5"- chloro 3 fiuorosaligenin (35.3 grams) and palladium on a charcoal: carrier (3 grams of a composition comprising 5 percent of palladium) were placed in a flask and subjected to a hydrogen atmosphere at a total pressure of 30 pounds per square. inch gauge. The flask was then placed on a commercial shak er and shakenforj'about 30 minutes (until a pres sure drop of about 15.5pounds per square inch indicated the'reaction of about 0.2 mol of hydrogen). The catalyst was separated from the. liquid by filtration, and the filtrate was acidified by hydrochloric acid (50 cc. of a 30 per cent solution). The acidified liquid was saturated with sodium chloride; the crystals ofB-fluorosalijgenin precipitated and were separated byfiltration. These crystals were dissolved in acetone (200 cc.),, and salt was separated from theaceton solution by filtration. The filtrate was. placed in an evaporating dish andtheacetone was allowed to evaporate leaving the dry 3-fluorosaligenin (18' grams). This corresponds to a 6d per cent yield of thedesired product.

' Example 2 A new compound (4-chloro-alpha-diinethylannno6-fiuoro-o-cresol) was 'prepared'as an in: termediate needed in the practice. of the invention according to the following procedure; I 4-chloro-2-fiuorophenol (1042 grams) and di-' methyl ainine (2615 grams of a per cent aqueone solution) were added to a flask and the. mixture was cooled to C. Aqueous formaldehyde (9. total of 6281grams of a per cent aqueous solution) was added stepwise with stirring to this mixture. The formaldehyde wasadded at, such a rate that the temperature of the mixturedid not rise above f C. When the addition of formaldehyde'was'completejthe mixture was stirred thoroughly and was heated on a steam hath cry of the desired i-chloro-alpha-dimethyl- ':amino-d-fiuorwmciresol amounted to 1376 grams which corresponds to a 95 per cent yield based on, the, i chloro-2-fluorophenol charged. The

' 4 chloro -alpha-dimethylamino-6-fiuoro-o-cresol is believed to be a new compound; its melting boiling point 134 0. to 136 C. at an absolute pressure of 4 min. of mercury) is believed to be a new compound.

3-fiuorosaligenin diacetate was produced according to the following procedure: l

A sample of 5'-chloro'-3-fluorosaligenin diacetate (26 grams) was'mixed with methanol (150 7 indicated the reaction of'about0;l5 mol of hydrogen); the catalyst was removed from the solution by filtration; and the solvent was evaporated by a reduced; pressuredistillationin the course. of :which'the temperature was maintained below C. -The. .residue from this reduced pressure distillation was identified as li -fluorosaligenin di-- acetate. r V

5 We claim: 1. A methodof producing a compound having the general formula CHaOR in which each of the radicals R and R is ofthe class consisting of hydrogen and acetyl' which method comprises dechlorinating a saligenin derivative havingthe general formula CHnOR Cl E in which R and B have the meanings: hereinbefore set forth, by the action of one mol of gaseous hydrogen per mol' of the saligenin derivativeat a pressure of from about 10 to about 40 pounds per square inch gauge, and in the pres-.

the hydrogen pressure is not greater than 30 l pounds per square inch gauge. I 0

4. -A method as claimed in claim .1' in whic each of the radicals R and R is hydrogen.

zfi jchem. (1949), pulsar-s59.

5. A method as claimed in claim 4 in which the hydrogen pressure is not greater than 30 1 pounds per square inch gauge.

EDGAR C. BRITTON.

JAMES D. HEAD.

References Cited in the file of this patent Remick, Electronic Interpretation of Organic Kelber, Berichte der deut. Chem. GeselL, vol. 

1. A METHOD OF PRODUCING A COMPOUND HAVING THE GENERAL FORMULA 